Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study

Abstract

Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.

Association between human blood metabolites and cerebral cortex architecture: evidence from a Mendelian randomization study

“…This metabolic pathway affects aspartate, glutamate, and γ-aminobutyric acid (GABA) levels, which play key roles in early brain development ( 46 ). In addition, the involvement of the arginine biosynthesis and aspartate and glutamate metabolism has been identified in studies involving epilepsy, schizophrenia, AD animal models, and blood samples ( 47–50 ). Our study provides a stronger validation of these conclusions.…”

Deciphering the Metabolic Shifts in The Hippocampus of Mice Subjected to Near Low Dose Radiation: Insights from Metabolomics and Integrated Multi-omics

“…Tyrosine metabolism directly regulates the synthesis of L-DOPA to dopamine and indirectly regulates the synthesis of norepinephrine (Herman et al 2019). Alterations in phenylalanine can cause modifications in the levels of catecholamine neurotransmitters (Fernstrom and Fernstrom 2007), while altered arginine metabolism has been linked to tauopathy (Mein et al 2022). Furthermore, glutathione metabolism is crucial in providing defense against ROS and protecting neurons (Dringen et al 2000).…”